The study of oncogenes holds considerable promise in elucidating the mechanism of the disease of cancer, and leading to improved pharmaceutical treatments. Oncogenes and their products appear to be associated with the transformation of cells to malignancy through growth control pathology. While the occurrence of oncogenes was first detected in retroviruses, it has been established that many viral oncogenes have cellular counterparts (for a review, see Tronick and Aaronson, Oncogenes Growth Regulation and Cancer in Advances in Second Messenger and Phosphoprotein Research, 28:201 (1988)). While only a small number have a known physiological function, this knowledge has provided important insights about how oncogenes and protooncogenes work in both normal and malignant cells.
Over 50 oncogenes have been thus far identified, many of which have properties of growth factor receptors (e.g., erbB, erbB-2, fms, kit, trk, met, ret, ros, sea, eph, eck, elf, and flg). These properties include an extracellular domain, ligand binding domain, transmembrane region, and an intracellular domain that exhibits tyrosine kinase activity. The erbB gene was found to share strong homology with the epidermal growth factor (EGF) receptor (Downward et al., Nature, 307:521-527 (1984)) and fms was shown to be homologous to the receptor for colony stimulating factor-1 (Sherr et al., Cell, 41:665-676 (1985)). Recently, ligands for c-erbB-2 (Lupu et al., Science, 249:1552-1555 (1990)), and c-kit (Flanagan and Leder, Cell, 63:185-194 (1990)); Nocka et al., EMBO J., 9:3287-3294 (1990); Zsebo et al., Cell, 63:213-224 (1990)) have been reported.
There is now mounting evidence that tumorigenicity is closely correlated to the presence and level of expression of these cell-surface oncogenes. Both the existence and enhanced expression of the oncogene proteins may result from alterations including genetic rearrangements, point mutations, or amplifications at the deoxyribonucleic acid (DNA), the ribonucleic acid (RNA), or protein levels (Bishop, Science, 235:305 (1987); DiFiore, et al. Science, 237:178 (1987); Slamon, et al. Science, 235:177 (1987); Krause, et al., The EMBO Journal, 6:605 (1987); and Der, Clinical Chemistry, 33:641 (1987)). While many of these oncogene proteins are present on the surface of some normal cells (such as in the case of c-erbB-2), the amplification or overexpression of oncogenes has been shown to correlate with tumorigenic activity. In fact, the amplification of the c-erbB-2 oncogene indicates a very poor clinical prognosis, especially in breast and ovarian cancer (Slamon, et al., Science 235:177 (1987) and Slamon, et al., Science, 244:707 (1989)).
A wide range of anti-neoplastic drugs have been identified for cancer therapy. Considerable difficulties, however, are encountered with the use of these drugs because of their toxicity to normal tissue. Monoclonal antibody technology brought with it a promising tool to attempt to specifically target cancer cells. Most of the clinical studies to date using this technology for cancer treatments have been disappointing, however, for many reasons, including the requirement for large doses to deliver sufficient drug to the cancer cells. Such large doses result in toxic side effects largely due to non-specific binding to normal cells and processing of the drugs by the liver. Thus, there exists a continuing need for safer and more effective treatments to eliminate and control tumor cell growth.